Inflammation has been linked to cancer formation and progression in part because having a chronic inflammatory diseases increases a person's risk of developing cancer. Recent work has demonstrated that inflammation causes alterations in DNA methylation, microRNA expression, and, on a global level, histone marks. Since by definition these epigenetic changes are mitotically heritable and affect gene expression, they likely play a role in establishing disease phenotypes. Because epigenetic changes are reversible by using an expanding array of epigenetic inhibitors, understanding these epigenetic changes is key to the development of future prevention and treatment strategies for diseases associated with chronic inflammation, including cancer. Changes in DNA methylation, which have been the focus of most studies of the epigenetic responses to inflammation to date, are thought to be a final stage of epigenetic modification. During carcinogenesis, aberrant gains in promoter DNA methylation transcriptionally silence tumor suppressor genes, linking DNA methylation directly to tumorigenesis. However, it is unknown what the mechanisms of targeting and initiation are for these stable cancer-specific epigenetic marks. At sites of inflammation, there are high levels of reactive oxygen species (ROS) that can create oxidative damage. To begin to understand the mechanism of initiation of epigenetic changes, we used both in vitro and in vivo models to link oxidative DNA damage to acute changes in the interaction of epigenetic silencing proteins with each other and the chromatin, suggesting that one role of oxidative damage in disease may be to initiate epigenetic changes. However, these findings still do not directly link inflammation to epigenetic changes, nor to more permanent disease-specific epigenetic changes. The central hypothesis for my current research is that inflammation-induced oxidative damage causes acute genome-wide changes in the binding of epigenetic silencing proteins that result in the permanent epigenetic silencing of genes in tumors that form at the sites of exposure. In our murine model, mice are infected with the human commensal enterotoxigenic Bacteriodes fragilis, ETBF, which causes acute inflammation, chronic colitis, and tumorigenesis. Preliminary data demonstrates that the epigenetic silencing proteins EZH2 and DNMT1 are recruited to the promoters of key genes during acute oxidative damage induced by this toxigenic bacterial infection and, in tumors that form at the sites of exposure, persistence of these epigenetic changes can be detected. Although this work currently focuses on colon tumorigenesis, the mechanism of oxidative damage-induced epigenetic changes is likely to be applicable to other sites of inflammation-induced tumorigenesis as well. My long-term goal is to gain a better understanding of the mechanism and molecular progression of inflammation-induced epigenetic changes to be able to develop treatments that reverse these epigenetic changes after exposure and therefore prevent disease formation.